The primary focus of this Phase II proposal is development of a product against Alzheimer's disease (AD). AD is an increasingly important cause of morbidity and mortality in both hospital and long term nursing homes as well as in family environments. The direct and indirect cost of AD has been conservatively estimated at $149 billion in the U.S. Medicare expenditures alone are expected to increase to $160 billion by 2010. There is not yet any treatment that can delay or stop the deterioration of brain cells in AD. In the Phase I project, murine monoclonal antibodies (mAbs) were generated against the A??amyloid peptide. The binding of these mAbs to different conformational aggregates of A??was measured and a number of mAbs that recognize soluble oligomers of A??with high affinity were identified. These mAbs were produced at high levels as mouse-human hybrids in a unique plant expression system. In addition, a phage display library of human ScFvs was constructed in order to identify additional unique antibodies resulting from a human autoimmunity. In Specific Aim 1 of this proposal, new human mAbs will be evaluated and compared to the existing hybrids. The best five antibodies from this population will be tested in vivo in APPswe/PS1dE9 transgenic mice to assess the impact of injected antibody on murine cognitive function (Specific Aim 2). In Specific Aim 3, the best mAb of the group will be produced in a GMP facility for use in IND-enabling studies to support a Phase 1 safety trial. In the final aim, Specific Aim 4, the cGMP produced mAb will be used to complete Investigational New Drug (IND) enabling studies (pharmacology and toxicology, CMC) to enable an IND submission. More than 5 million people in the U.S. currently have Alzheimer's disease (AD). At this time, there is no treatment that can delay or stop the deterioration of brain cells in AD. The aim of this proposal is to develop new antibody-based therapies for AD that, it is hoped, will ultimately act to both prevent and treat the disease. The experiments in the proposal will provide the foundation for clinical evaluation of these potential therapies to ensure their safety and efficacy.